Herpes simplex virus 2 (HSV-2) causes genital herpes and increases the risk of transmission and infection with HIV. Thus a vaccine for HSV-2 would not only reduce the rate of genital herpes, but also might reduce spread of HIV. Several HSV-2 vaccines have been tested in humans for prevention or reduction of genital herpes disease. A vaccine containing a single viral protein (HSV-2 glycoprotein D) recently showed no evidence for protection against genital herpes in a large international, phase three, randomized controlled trial in HSV-2 seronegative women. We postulate that the limited efficacy of the HSV-2 glycoprotein D vaccine is likely due to inadequate induction of broadly neutralizing antibody and cellular immune responses. Last year we reported that we constructed an HSV-2 mutant with changes in the HSV-2 glycoprotein D (gD) that impair the ability of gD to interact with one of its receptors, nectin-1, but not with another receptor, HVEM. This mutant virus was able to infect cells expressing HVEM (epithelial cells), but not cells only expressing netin-1 (neuroblastoma cells). The mutant did not productively infect dorsal root ganglia in the nervous system of mice. The inability of the HSV mutant to productively infect neuronal cells in culture or ganglia in mice after intramuscular inoculation suggests that the HSV-2 mutant might be an attractive candidate as a live attenuated HSV-2 vaccine. This year we initiated a phase 1 clinical trial to test the safety and immunogenicity of a different vaccine, a replication-defective HSV-2 vaccine, in humans. This vaccine was developed by Dr. David Knipe at Harvard, and our lab performed much of the preclinical work in mice and guinea pigs. We also tested the ability of interleukin-1 (IL-1) to serve as an adjuvant to enhance the effectiveness of an HSV-2 gD vaccine. We found that mice receiving HSV-2 gD with IL-1 combined with alum and monophosphoryl lipid A(MPL) adjuvant had improved survival after challenge with HSV-2 compared with animals receiving gD with alum and MPL.